Engineering non-antibody scaffolds and growth factor ligands as protein therapeutics and diagnostics
Abstract/Contents
- Abstract
- Protein therapeutics have emerged as an important class of pharmaceuticals, with monoclonal antibodies making up the largest group of protein drugs. While antibodies have many desirable characteristics, there are some applications in which they may be the best option. In this dissertation, we describe alternative classes of proteins that can complement the use of antibodies in the development of protein therapeutics and diagnostics. Cystine knots, or knottins, have highly desirable properties for use as molecular imaging agents due to their small size and stable structure. Previous approaches to engineering knottins have focused on a small subset of knottin scaffolds; in this work we extend those studies to engineering Agatoxin, a knottin from spider venom, for high affinity binding to tumor associated integrins. Growth factor ligand-receptor interactions modulate many cell signaling pathways and biological processes. The vascular endothelial growth factor (VEGF) and the platelet-derived growth factor (PDGF) mediate two important signaling pathways involved in angiogenesis. In this work, we used the structural similarity of PDGF and VEGF to rationally design a chimeric PDGF/VEGF ligand, creating a multi-specific antagonist of their receptors PDGFR and VEGFR. The PDGF/VEGF chimera was then engineered using combinatorial methods, including yeast surface display, for increased binding affinity to PDGFR and VEGFR. The resulting engineered protein variant strongly inhibited PDGFR and VEGFR signaling with in vitro cell models. Given the important roles of PDGFR and VEGFR in angiogenesis, the PDGF/VEGF chimera has potential application in anti-angiogenesis therapy. Collectively, the engineered proteins in this work demonstrate the promise of using non-antibody scaffolds and growth factor ligands for the development of protein therapeutics and diagnostics.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2015 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Leung, Cheuk Lun |
|---|---|
| Associated with | Stanford University, Department of Chemical Engineering. |
| Primary advisor | Cochran, Jennifer R |
| Primary advisor | Swartz, James R |
| Thesis advisor | Cochran, Jennifer R |
| Thesis advisor | Swartz, James R |
| Thesis advisor | Khosla, Chaitan, 1964- |
| Advisor | Khosla, Chaitan, 1964- |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Cheuk Lun Leung. |
|---|---|
| Note | Submitted to the Department of Chemical Engineering. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2015. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2015 by Cheuk Lun Leung
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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